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Nature. 2014 Aug 14;512(7513):190-3. doi: 10.1038/nature13425. Epub 2014 Jun 18.

A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes.

Author information

1
1] The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark [2] Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA [3].
2
1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark [2].
3
Steno Diabetes Center, 2820 Gentofte, Denmark.
4
National Institute of Public Health, University of Southern Denmark, 1353 Copenhagen, Denmark.
5
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
6
Department of Integrative Biology, University of California, Berkeley, California 94720, USA.
7
Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark.
8
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
9
1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark [2] Department of Molecular Medicine and Surgery, Karolinska Institute, 171 77 Stockholm, Sweden.
10
Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark.
11
BGI-Shenzhen, Shenzhen 518083, China.
12
1] BGI-Shenzhen, Shenzhen 518083, China [2] The Department of Genetic Medicine, Faculty of Medicine and Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
13
1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark [2] BGI-Shenzhen, Shenzhen 518083, China [3] The Department of Genetic Medicine, Faculty of Medicine and Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia [4] Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark [5] Macau University of Science and Technology, Macau 999078, China.
14
Holbaek Hospital, 4300 Holbaek, Denmark.
15
1] Department of Integrative Biology, University of California, Berkeley, California 94720, USA [2] Department of Statistics, University of California, Berkeley, California 94720, USA.
16
The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
17
1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark [2] Faculty of Health Sciences, University of Southern Denmark, 5000 Odense, Denmark.

Abstract

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l(-1), P = 2.5 × 10(-35)) and serum insulin (β = 165 pmol l(-1), P = 1.5 × 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = -0.18 mmol l(-1), P = 1.1 × 10(-6)) and fasting serum insulin (β = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l(-1), P = 5.3 × 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

PMID:
25043022
DOI:
10.1038/nature13425
[Indexed for MEDLINE]

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